GB2373245A - Pyridinyl pyrazoles and their use for the treatment of COPD - Google Patents

Abstract

The invention relates to the compounds of formula I<BR> wherein 'A' represent C, or N; 'D' represents a C<SB>5-10</SB> embrocyclic ring which can contain up to 3 atoms selected from N, O, or S; R<SB>1</SB>-R<SB>4</SB> represent H or substituent groups, and R<SP>5</SP> represents a C<SB>1-6</SB> alkyl group. These compounds are used for the treatment of COPD.

Description

Pvridinvl pvrazoles The present invention relates to Pyridinyl pyrazoles, processes for their preparation and their use in medicaments, especially for the treatment of COPD.

COPD is characterised by a neutrophil and macrophage inflammatory burden in the lung. Unlike asthma it has been shown that the inflammation (cells, IL-8, TNF) and airflow obstruction characteristic of COPD is insensitive to therapy with steroids.

The critical chemokine driving neutrophilic inflammation is believed to be IL-8, which can be released by a variety of human cells including bronchial epithelial cells, neutrophils and alveolar macrophages.

There are 3 major stress-activated protein kinase pathways l) p38 mitogen-activated protein (MAP) kinase ; 2) extracellular-regulated protein kinase (ERK) ; 3) c-Jun NH2 terminal kinase (JNK). Activation of human neutrophils and human bronchial epithelial cells results in a rapid activation of p38 MAP kinase which subsequently phosphorylates specific transcription factors, resulting in the synthesis and secretion of inflammatory mediators, particularly IL-8. Studies in vitro with the reference p38 MAP kinase inhibitor, SB 203580, have shown that the release of IL-8 from activated neutrophils and bronchial epithelial cells is linked to the activation of the p38 MAP kinase cascade. The exposure of human bronchial epithelial cells to cigarette smoke extracts also appears to increase the ability of p38 MAP kinase inhibitors to reduce IL-8 release suggesting that exposure to cigarette smoke in vivo may prime the p38 MAP kinase pathway of IL-8 release. These studies suggest that inhibition of p38 MAP kinase may be involved in regulating IL-8 release through an effect on gene expression. Inhibition of p38 MAP kinase may offer an alternative approach to IL-8 antagonism, and may thus provide an effective anti-inflammatory therapy for COPD.

The invention therefore relates to compounds of general formula (1), Le A 35030 HO/bv/NT

wherein

Rj and R2 represent hydrogen, halogen, Cl-C4-alkyl or Cl-C4-alkoxy, wherein Cl-C4-alkyl or C1-C4-alkoxy can optionally be substituted with up to 3 halogen atoms,

R represents hydrogen, halogen, N-bound heterocyclyl, hydroxy, Ci-Ce-alkoxy or C1-C6-alkyl, wherein Cl-C6-alkoxy or Cl-C6-alkyl can optionally be substituted with up to 3 halogen atoms, or

, 3 3-1 3-2 3-3-4 R3 represents-NR R,-COR or-S02R3 wherein R3-1 represents hydrogen, Cl-C6-alkyl, C3-C6-cycloalkyl, C6-Cio-aryl, heteroaryl, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, C3-C8-cyclo alkylcarbonyl, C6-C10-arylcarbonyl, heteroarylcarbonyl, C1-C6-alkyl sulfonyl, C3-C8-cycloalkylsulfonyl, C6-C10-arylsulfonyl, heteroaryl sulfonyl, R3-2 represents hydrogen, Cl-C6-alkyl, C3-C6-cycloalkyl, C6-cw-aryl, hetero

aryl, Cl-C6-alkylcarbonyl, Cl-C6-alkoxycarbonyl, C3-C8-cycloalkylcarbonyl, C6-Cio-arylcarbonyl, heteroarylcarbonyl, Cl-C6-alkyl LeA35030HO/bv/NT

sulfonyl, C3-Cs-cycloalkylsulfonyl, C6-Clo-arylsulfonyl, heteroarylsulfonyl, R3-3 represents hydrogen, hydroxy, Cl-C6-alkyl, C3-C6-cycloalkyl, Cl-C6- alkoxy, C6-C10-aryloxy, C6-C10-aryl, heteroaryl, amino, Cl-C6-alkyl-

amino, Cl-C6-dialkylamino, C3-C6-cycIoalkyIamino, C3-C6-bis-cycloalkylamino, Ce-Cio-arylamino, C6-Clo-bis-arylamino, heterarylamino, 3-sulfolanylamino, N-bound heterocyclyl, R represents hydroxy, CrC6-alkyl, C3-C6-cycloalkyl, C6-Cio-aryl, heteroaryl, amino, CrCe-alkylamino, Cl-C6-dialkylamino, C3-C6-cycIoalkylamino, C3-C6-bis-cydoalkylammo, C6-Cio-arylamino, Cg-Ciobis-arylamino, heteroarylamino, N-bound heterocyclyl, and wherein carbon atoms ofR3 can optionally be substituted with up to three halogen atoms, R4 represents hydrogen, halogen or Cl-C4-alkyl, or R3 and R4 together with the carbon atoms to which they are attached form a [N (C1-C6) alkylcarbonyl]-pyrrolidin ring R5 represents C1-C4-alkyl A represents carbon or nitrogen, D represents a 5-to 10-membered aromatic ring, which can contain up to 3 heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, Le A 35 030 HO/by/NT

or pharmaceutically acceptable salts thereof.

In the context of the present invention, the substituents, if not stated otherwise, in general have the following meaning : Alkyl in general represents a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl. The same applies to radicals such as alkylcarbonylamino or Ci-C6-alkylamino.

Alkoxy in general represents a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms and bound via an oxygen atom. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy. The terms"alkoxy"and"alkyloxy"are used synonymously.

Cycloalkyl in general represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. Non-limiting examples include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Aryl represents a 6-to 10-membered, mono-or bicyclic ring system, which is aromatic at least in one ring. Examples are : phenyl, naphtyl.

In the context of the present invention, heterocyclyl stands for a a saturated or partially unsaturated heterocyclic ring which can contain l to 3 heteroatoms selected independently from the group consisting of nitrogen, oxygen or sulfur such as tetrahydrofuran, pyrrolidin, piperidin, morpholin. It can be attached via a ring nitrogen atom (N-bound") In the context of the present invention, a 5-to 10-membered aromatic heterocyclic ring (heteroaryl"), which can contain 1 to 3 heteroatoms selected independently from the group consisting of nitrogen, oxygen or sulfur denotes a ring system, which Le A 35030 HOlbylNT

is mono-or bicyclic, is aromatic at least in one ring, and which can contain l to 3 of the abovementionend heteroatoms. It can be attached via a ring carbon atom.

Examples are : furan, pyridine, benzofuran, pyrazol, oxadiazol or benzoxazol.

Suitable pharmaceutically acceptable salts of the compounds of the present invention that contain an acidic moiety include addition salts formed with organic or inorganic bases. The salt forming ion derived from such bases can be metal ions, e. g., aluminum, alkali metal ions, such as sodium of potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, of which a number are known for this purpose. Examples include ammonium salts, arylalkylamines such as dibenzylamine and N, N-dibenzylethylenediamine, lower alkyl amines such as methylamin, tbutylamine, procaine, lower alkylpiperidines such as N-ethylpiperidine, cycloalkylamines such as cyclohexylamin or dicyclohexylamine, 1-adamantylamine, benzathine, or salts derived from amino acids like arginine, lysine or the like. The physiologically acceptable salts such as the sodium or potassium salts and the amino acid salts can be used medicinally as described above and are preferred.

Suitable pharmaceutically acceptable salts of the compounds of the present invention that contain a basic moiety include addition salts formed with organic or inorganic acids. The salt forming ion derived from such acids can be halide ions or ions of natural or unnatural carboxylic or sulfonic acids, of which a number are known for this purpose. Examples include chlorides, acetates, trifluoroacetates, tartrates, or salts derived from amino acids like glycine or the like. The physiologically acceptable salts such as the chloride salts, the trifluoroacetic acid salts and the amino acid salts can be used medicinally as described below and are preferred.

In a preferred embodiment, the invention relates to compounds of general formula

(1), wherein

Rj and R2 represent hydrogen, halogen, Ci-C4-alkyl or C]-C4-alkoxy, wherein Cl-C4-alkyl or Ci-C4-alkoxy can optionally be substituted with up to 3 halogen atoms, R represents hydrogen, halogen, Cl-C6-alkyl, which can optionally be substi tuted with up to 3 halogen atoms, or R3 represents Ci-C6-alkylcarbonylamino, Ci-C6-dialkylcarbonylamino amino, C6-C10-arylcarbonylamino, C3-C8-cycloalkylcarbonylamino, Cl-C6-alkyl- amino, Ci-C6-dialkylamino, C3-C6-cycloalkylamino, C6-Cio-arylamino, C1-C6-alkoxycarbonylamino, carboxyl, CrC6-alkoxycarbonyl, amino

carbonyl, C]-C6-alkylaminocarbonyl, Ci-C6-dialkylaminocarbonyl, C6-arylaminocarbonyl, 3-sulfolanylaminocarbonyl, Ct-C6-alkylsulfonylamino, aminosulfonyl, Ct-C6-alkylaminosulfonyl, Cl-C6-dialkylaminosulfonyl, C3-Cs-cycloalkylaminosulfonyl, N-pyrrolidinylsulfonyl, N-morpholinyl, 1, 2, 3-triazol, hydroxy, Ci-C6-alkoxy, wherein Crue-alkoxy can optionally be substituted with up to 3 halogen atoms, R4 represents hydrogen or Cl-C4-alkyl, R5 represents methyl, A represents carbon or nitrogen, D represents a phenyl, o-pyridyl, benzofuranyl, indolyl or thiophenyl ring, and wherein

substituents R3 and/or R4 are in meta-or para-position relative to the exocyclic amino group.

In a more preferred embodiment, the invention relates to compounds of general formula (I), wherein R1 and R2 represent hydrogen, halogen, Cl-C4-alkyl or Ci-C4-alkoxy, wherein Cl-C4-alkyl or C !-C4-alkoxy can optionally be substituted with up to 3 halogen atoms, R3 represents hydrogen, halogen, Cl-C6-alkyl, which can optionally be substi tuted with up to 3 halogen atoms, or R3 represents C)-C6-alkylcarbonylamino, amino, C1-C6-alkylamino, Cl-C6-di-

alkylamino, aminocarbonyl, CrC6-alkylaminocarbonyl, Cl-C6-dialkylaminocarbonyl, C6-arylaminocarbonyl, C]-C6-alkylsulfonylamino, aminosulfonyl, Cl-C6-alkylaminosulfonyl, Cl-C6-dialkylaminosulfonyl, Cl-C6-alkylsulfonyl amino, R4 represents hydrogen or C)-C4-alkyl R5 represents methyl A represents carbon or nitrogen, D represents phenyl.

In a very preferred embodiment, the invention relates to compounds of general formula (I), wherein A represents carbon.

In another very preferred embodiment, the invention relates to compounds of general formula (I), wherein R represents methyl.

In another very preferred embodiment, the invention relates to compounds of general formula (I), wherein R'represents methyl or fluoro.

In another very preferred embodiment, the invention relates to compounds of general formula (I), wherein R3 represents aminosulfonyl, aminocarbonyl or methylsulfonylamino.

In another very preferred embodiment, the invention relates to compounds of general formula (I),

wherein substituents R3 and/or R4 are in para-position relative to the exocyclic amino group.

Surprisingly, the compounds of the present invention show p38 MAP kinase inhibitory activity and are therefore suitable for the preparation of medicaments for the treatment of diseases associated with p38 MAP kinase. They may thus provide an effective treatment of acute and chronic inflammatory processes and an antiinflammatory therapy for COPD.

Related analogues of the p38 lead compound SB-2033580 have been shown to be potent inhibitors of a number of human liver P450 enzymes (J. C. Boehm et al. Expert Opinion on Therapeutic Patents, 2000, 10, 25). Many of the compounds of the present invention show an improved profile with respect to the inhibitory potency towards human CYP isoforms. The less pronounced in vitro inhibiton of CYP isoforms can make clinically relevant drug-drug interactions less likely and these compounds more suitable as antiinflammatory agents.

P 38 map kinase assay The assay makes use of the serine/threonine protein kinase SPA [33-P] +assay kit from Amersham Pharmacia Biotech. The assay is a homogeneous technique using SPA technology for the quantification of serine threonine kinase activity.

It is based on the p38 map kinase catalysed transfer of the y-phosphate group of the [y-P] ATP to the substrate, biotinylated myelin basic protein (MBP). The resulting [3P]-labelled biotinylated product is trapped on a PVT SPA bead containing scintillant which has been surface coated with streptavidin.

The beads are allowed to settle to eliminate high background, and therefore only 33p labelled product attached to the SPA bead is detected.

The assay is carried out in the presence and absence of test compounds to determine their effect on p38 map kinase activity.

A test protocol is as follows : 1. SPA assay kit (Amersham). Components - Assay buffer (store frozen) - Stop solution (store frozen) - Streptavidine coated SPA beads-reconstitute with 5 mls of PBS.

(50mg/ml). (Store in fridge)

2. p 38 map kinase enzyme SCRD (260ug/ml)-aliquoted in 1. 5 mls.

- dilute 1 : 5. 2 to 50ug/ml - 1 plate :-193nul (stock 260ug/ml) + 810. 6ul PBS.

3. Assay reagent : - for 1 plate :- 504 l Assay buffer (500Mm MOPS pH7.2, 10aM ATP, 50mM MgCl2, 25 M biotinylated myelin basic protein (MBP)).

- 2518. 4 l Water - 1. 1 l 33-p-ATP (10 Ci/ul) (on activity date/adjust for activity date) 4. Stop solution : - for 1 plate :- 221.6 l streptavidin coated beads (50mg/ml) - 1376. 4ill stop buffer (500 M ATP, 50mM EDTA 1% Triton X-100) - 5903.6 l PBS.

1. Add 10 l compound Dilutions (5x final conc) Test wells.

2. Add 10 l 12. 5% DMSO to control/blank wells.

3. Add 10 l enzyme (50ug/ml)-final conc 500ng/well 4. Add 10 l PBS to blank wells.

5. Add 301 of assay reagent to each well. (final conc lM ATP, 2. 5uM substrate) 6. Mix well on plate shaker 7. Incubate on bench 90 min (room temperature) 8. Add 75ill of stop solution to each well (final conc 55M ATP) 9. Spin plate :-3min/1600rpm/20 C (alternatively leave to settle overnight) 10. Read in topcount Representative Data are given in table 1 :

Ex. No. IC50( M) 1 0. 13 2 0. 066 5 0. 48 43 0. 058 50 0. 31 56 0. 084 table 1 Description of the functional Assays Neutrophils are isolated from human blood via discontinuous Percoll gradient and seeded at 1x106 cells/well. Compounds are added, and the cells are incubated for Ih at 37 C. After 1h, cells are stimulated with TNF-alpha (25ng/ml final conc.) for 18h. Supematants are harvested and analysed for IL-8 content by ELISA.

Description of the in vivo model Mouse LPS/KC method Dosing vehicle : 20% saline.

Le A 35 030 HO/by/NT

Method of preparation of test substance : The test substance is ground into a fine powder using a pestle and mortar. Solutol/Ethanol mixture is then added and the compound ground until no visible particles remain. Saline is added to make the final concentration of0. 75mg/ml.

Animals : Species : Mouse Strain : Balb/C Experimental protocol : 1. Compound administration. Animals are given vehicle, or compound i. v. 5 minutes before saline or LPS i. n.

2. i. n. challenge. Animals are lightly anaesthetised (isofluorane/02) and LPS (2ug/ml) or sterile saline given i. n at a dose volume of 251/nare. They are then allowed to recover in a heated box (28 C) before return to their home cage.

3. BAL. Animals are killed 1 or 4 hours after i. n. challenge with and i. p. overdose or sodium pentobarbitone (0.2ml). BAL fluid collected (3xi. 3ml aliquots hep/PBS (lOU/ml), spun down (microfuge 10 minutes) and the supernatants frozen for later KC assay (following kit instructions).

Health Status monitoring : Animals are monitored for adverse effects (using a distress scoring sheet as necessary).

Statistical methods : Data are analysed using Mann Whitney U test.

P 450 test Microtiter plate-based, fluorometric assays for the activities of five principal drugmetabolizing enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 can be used. Two direct fluorometric assays are used using 3-cyano-7-ethoxy

coumarin [CEC2 (7)] as a substrate for CYPIA2, CYP2C9, CYP2C19, and CYP2D6 and resorufin benzyl ether [BzRes (8)] as a substrate for CYP3A4. Baculovirus/insect T A Q n TJn., X

cell-expressed enzymes of high catalytic activity permits the use of these substrates which are slowly metabolized (per unit enzyme) for all enzymes except CYP1A2. Assays are conducted in 96-well microtiter plates Catalog No. 3598, Coming Costar, Cambridge, MA). The substrates, BzRes and CEC (Molecular Probes, Eugene, OR), are prepared as homogeneous suspensions in pH 7.4 to 7.5 buffer (potassium phosphate for all enzymes except for CYP2C9 which used Tris) by sonication (three bursts, Bransonic 250 sonifier, power level of 7). The substrate stock concentrations are twice final concentration [final concentration is chosen to be approximately the apparent Km). The 12 wells in a row are used for one inhibitation curve. Wells 1 to 8 contain serial 1 : 3 dilutions of the inhibitors. Wells 9 and 10 contain no inhibitor and rows 11 and 12 are blanks for background fluorescence (stop solution is added before the enzyme). The final volume of substrate/inhibitor is 0.1 ml. Furafyline and sulfaphenazole are obtained from Ultrafine Chemicals Manchester, UK). All other chemicals are obtained from Sigma Chemical Co. (St. Louis, MO). Methanol is used to initially dissolve furafylline, sulfaphenazole, tranylcypromine and ketoconazole.

Final solvent concentration is less than 1%. Quinidine is dissolved in water. After substrate and inhibitor addition, the plates are prewarmed to 37OC. Incubations are initiated by the addition of 0.1 ml of prewanned enzyme and cofactors (final incubation volume of 0. 2 ml). The enzymes are commercially available, baculovirus/inset cell-expressed human cyclochromes P450 (SUPERSOMES, GENTEST Corp., Wobum, MA). The final cofactor concentrations are 1.3 mM NADP, 3. 3 mM glucose 6-phosphate, and 0. 4 U/ml glucose-6-phosphate dehydrogenase (all from Sigma Chemical Co. ). Final incubation volume was 0.2 ml.

Incubations are carried out for 30 min (CYP1A2 and CYP3A4) or 45 min (CYP2C9, CYP2C19, and CYP2D6) and stopped by the addition of 0. 1 ml of 60% acetonitrile, 40% 0.1 M Tris, pH 9. Metabolite formation is linear for these incubation times.

Fluorescence per well is measured using a CytoFluor Model 2350 fluorescent plate reader (Millipore, Bedford, MA) controlled with an IBM-compatible 486DX2 computer. The CEC metabolite, 3-cyano-7-hydroxycoumarin, is measured using an excitation of Le A 35 030 HO/by/NT 485 nm (20-nm bandwidth). The BzRes metabolite, resorufin, is measured using and excitation wavelength of 530 nm (25-nu bandwidth) an emission wavelength of 590 nm (35-nm bandwidth). Detection of the products of either assay is linear over the range used for these assays. Data are exported and analyzed using an Excel spreadsheet. The ICso values are calculated by linear interpolation.

5 10 15

Representative Data are given in table 2 :

Ex. No. CYPIA2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 IC50 IC50 IC50 IC50 IC50 () M) (M) (M) (tiM) (M) /57'0243X) (L5 ci 57. 7 0. 6 2. 4 3. 0 0. 5 uN N 38. 5 0. 7 2. 1 3. 0 0. 7 NEC Nb HN r WO 99/58523 Example 24 l464ll7ll368J73 1 46. 4 13. 7 12. 3 68. 3 7. 3 45. 6 13. 4 11. 1 64. 9 7. 4 2 30. 8 8. 1 10. 5 23. 7 21. 7 43. 5 11. 8 14. 9 24. 3 22. 6

table 2 In another embodiment, the present invention relates to the composition containing at least one compound of general formula (I) and a pharmacologically acceptable diluent and the use of such composition for the treatment of acute and chronic inflammatory processes as well as the process for the preparation of such compositions, characterized in that the compounds of general formula (I) together with customary auxiliaries in brought into a suitable application form.

For the treatment of the above-mentioned diseases, the compounds according to the invention can exhibit non-systemic or systemic activity, wherein the latter is preferred. To obtain systemic activity the active compounds can be administered, among other things, orally or parenterally, wherein oral administration is preferred.

For parenteral administration, forms of administration to the mucous membranes (i. e. buccal, lingual, sublingual, rectal, nasal, pulmonary, conjunctival or intravaginal) or

into the interior of the body are particularly suitable. Administration can be carried out by avoiding absorption (i. e. intracardiac, intra-arterial, intravenous, intraspinal or intralumbar administration) or by including absorption (i. e. intracutaneous, subcutaneous, percutaneous, intramuscular or intraperitoneal administration).

For the above purpose the active compounds can be administered per se or in administration forms.

Suitable administration forms for oral administration are, inter alia, normal and enteric-coated tablets, capsules, coated tablets, pills, granules, pellets, powders, solid and liquid aerosols, syrups, emulsions, suspensions and solutions. Suitable administration forms for parenteral administration are injection and infusion solutions.

The active compound can be present in the administration forms in concentrations of from 0. 001-100 % by weight ; preferably the concentration of the active compound should be 0.5-90% by weight, i. e. quantities which are sufficient to allow the specified range of dosage.

The active compounds can be converted in the known manner into the abovemen tioned administration forms using inert non-toxic pharmaceutically suitable auxiliaries, such as for example excipients, solvents, vehicles, emulsifiers and/or dispersants.

The following auxiliaries can be mentioned as examples : water, solid excipients such as ground natural or synthetic minerals (e. g. talcum or silicates), sugar (e. g. lactose), non-toxic organic solvents such as paraffins, vegetable oils (e. g. sesame oil), alcohols (e. g. ethanol, glycerol), glycols (e. g. polyethylene glycol), emulsifying agents, dispersants (e. g. polyvinylpyrrolidone) and lubricants (e. g. magnesium sulphate).

In the case of oral administration tablets can of course also contain additives such as sodium citrate as well as additives such as starch, gelatin and the like. Flavour en

hancers or colorants can also be added to aqueous preparations for oral administra tion.

For the obtainment of effective results in the case of parenteral administration it has generally proven advantageous to administer quantities of about 0. 001 to 100 mg/kg, preferably about 0.01 to 1 mglkg of body weight. In the case of oral administration the quantity is about 0.01 to 100 mg/kg, preferably about 0.1 to 10 mglkg of body weight.

It may nevertheless be necessary to use quantities other than those mentioned above, depending on the body weight concerned, the method of administration, the individual response to the active compound, the type of preparation and the time or interval of administration.

In another embodiment, the present invention relates to a process for synthesizing the compounds of general formula (I), characterized in that compounds of general formula (tri)

are reacted with compounds of general formula (III)

to yield compounds of general formula (I).

Example I Preparation of methyl 2-chloroisonicotinate (WO 99/58523) : To a solution of thionyl chloride (0.127 mol) in 20 mL of toluene is added 2chloroisonicotinic acid (10.0 g, 0.063 mol) and the reaction is heated at reflux until gas evolution ceases. Then a solution of methanol (7.7 mL, 0.19 mol) in 10 mL of toluene is added at room temperature over 15 min. The reaction mixture is then refluxed for 1 h and then cooled to room temperature. The clear solution is poured into 100 mL of water, basified with 40 % NaOH and extracted with ethyl acetate.

The organic layer is washed with brine, dried over magnesium sulfate and filtered.

The filtrate is concentrated in vacuo to the product as a brown oil which solidifies upon standing.

Preparation ofl- (2-chloroisonicotinyl)-l, 3-butanedione (WO 99/58523) : To solution of methyl 2-chloroisonicotinate (12.0 g, 0.07 mol) and acetone (12.2 g, 0.21 mol) in 100 mL of dry THF at 35 C is added sodium methoxide portionwise. After heating the reaction mixture at reflux for 4 h, the solvent is removed. The residue is dissolved with 500 mL of water, acidified with acetic acid to pH = 6 and extracted with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate and filtered. The filtrate is concentrated in vacuo to give the product as a brown solid.

Preparation of 4-fl- (1-Benzofuran-5-yl)-3-methvl-lH-pyrazol-5-yH-2-chloropyridine

To a solution of 1- (2-chloroisonicotinyl)-1, 3-butanedione (3. 30 g, 17 mmol) in 10 mL ethanol, 3.70 g (20 mmol) and 1- (1-benzofuran-5-yl) hydrazine hydrochloride and 1. 40 g (20 mmol) sodium bicarbonate were added. The reaction mixture was heated at reflux overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated. 4 g of crude product, which contained 30% of the isomer 4- [I- (l-benzofuran-5-yl)-5-methyl-lH-pyrazol- 3-yl]-2-chloropyridine were obtained and used without further purification.

IH-NMR (d6-DMSO) : 8.30 (d, 1H), 8.10 (m, 1H), 7.90-7. 00 (m, 6H), 6.80 (s, 1H), 2.30 (s, 3H)

1- (I-benzofuran-5-yI) hydrazine hydrochloride was obtained e. g. from the 1benzofuran-5-amine : 1) Nain02, conc. HCI ; 2) SnCl2*2H20, conc. HCI. The amine is described in Kakimoto et al. ; Nippon Kagaku Zasshi ; 74 ; 1953 ; 636.

In an analogous way were synthesised :

No. Starting material Structure yield IH-NMR (DMSO D6) II From 1- (2-chloroiso- éi 78 8. 40 (d, tir), 7. 30 (m, nicotinyl)-1, 3- 4H), 7. 10 (m, I H), butanedione and m-7. 00 (m, 1H), 6. 80 (s, methylphenylhydrazi") 1H), 2. 30 (s, 3H), N ne hydrochloride CI 2. 25 (s, 3H) III From 1- (2-chloro-4-Pcrude 8. 30 (d, 1H), 7. 40 (m, pyri diny I)-4-m ethy 1- 5R), 7. 10 (m, 1H), I CH 1, 3-pentanedione and--CH 6. 85 (s, 1H), 3. 00 (m, m-methylphenyl-IH), 2. 30 (s, 3H), N-' N hydrazine ci 1. 30 (d, 6H) hydrochloride IZz IV From 1- (2-chloro- F 41 8. 40 (d, IH), 7. 40 (m, isonicotinyl)-1, 3-""cH3 5H), 7. 10 (m, 1H), butanedione and p-6. 80 (s, 1H), 2. 30 (s, N fluorophenylhydra-3H) zine (without using sodium bicarbonate) V From 1- (2-chloroiso- N 62 8. 40 (d, 1H), 8. 30 (m, nicotinyl)-1, 3-""N"cH ! H), 8. 10 (m, 1H), butanedione and 2-/"\" 7. 80 (m, 1H), 7. 40 pyridinehydrazine NCI (m, 2H), 7. 20 (m, ci (without using 1H), 6. 80 (s, 1H), sodium bicarbonate) 2. 30 (s, 3H)

No. Starting material Structure yield IH-NMR (DMSO D6) VI From 1- (2- a 2. 3 and 2. 35 (2s, 6H), chloroisonicotinyl)-'j 7. 75 (s, IH), N-N 1, 3-butanedioncand rf'7. 1 (dd, J=5Hz and p-NV lHz, IH), 7. 15-7, 3 p-CI methylphenylhydrazi (AB-syst., J=8Hz, ne (without using 4H), 7. 35 (d, J=lHz, sodium bicarbonate) IH), 8. 3 (d, J=5Hz, IH) VII From 1- (2- 4a-2. 0 and 2. 15 (2s, 6H), f chloroisonicotinyl)-N-N 7. 0 (s, IH), 7. 35-7. 5 1, 3-butanedioneand n) (m, 4H), N 0-ci 7. 8 (dd, J=5Hz and methylphenylhydrazi 1Hz, IH), ne (without using 7. 85 (d, J=lHz, 1H), sodium bicarbonate) 8. 4 (d, J=5Hz, IH) VIII From 1- (2- off 8. 40 (d, IH), 7. 80chloroisonicotinyl)-/ 7. 50 (m, 4H), 7. 40 (s, 1, 3-butanedione and N-N 1H), 7. 20 (m, 1H), m-trifluoromethyl-"J 6. 80 (s, 1H), 2. 30 (s, phenylhydrazine ci 3H) (without using sodium bicarbonate) IX From 1- (2-chloroiso- 0"'"8. 40 (d, 1H), 7. 40nicotinyl)-1, 3-tek 6. 90 (m, 6H), 6. 80 (s, N-N butanedione and m- IH), 3. 80 (s, 3H), methoxyphenylhydra : : 2. 30 (s, 3H) zine (without using CI sodium bicarbonate)

table 3

Example 1 : 4- ( {4- [3-Methyl-l- (3-metbylpbenyl)-lH-pyrazol-5-yl]-2-pyridinyl}amino) benzamide

2-Chloro-4-[3-methyl-l- (3-methylphenyl)-IH-pyrazol-5-yl]pyridine (100 mg, 0. 35 mmol) (WO 99/58523) and 4-aminobenzamide (58 mg, 0. 42 mmol) are mixed and heated under argon at 190 C for 20 hours.

Chromatography yielded 25 mg (18, 5%) 4- ( {4- [3-methyl-l- (3-methylphenyl)-lHpyrazol-5-yl]-2-pyridinyl} amino) benzamide.

1H-NMR (d6-DMSO) : 9. 40 (s, 1H), 8. 20 (d, 1H), 7. 80 (m, 3H), 7. 60 (d, 2H), 7. 20 (m, 4H), 7. 00 (m, IH), 6. 70 (s, IH), 6. 50 (m, 2H), 2. 30 (s, 3H), 2. 25 (s, 3H) Example 2 : 4- ( {4- [1- (4-fluorophenyl)-3-methyl-lH-pyrazol-5-yi]-2-pyridinyl}amino) benzenesul fonamide

1.05 g (3.65 mmol) 2-Chloro-4-[1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]pyridine and (4.38 mmol) 4-aminobenzenesulfonamide are mixed and heated under argon at 190 C for 1 hour. Chromatography yielded 478 mg (31%) 4-({4-[3-methyl-1-(3 methylphenyl)-1 H-pyrazo !-5-yl]-2-pyridinyl} amino) benzamide.

1H-NMR (d6-DMSO) : 9.5 (s, IH), 8.2 (d, IH), 7.8-7. 6 (m, 4H), 7.4-7. 2 (m, 4H), 7.25 (s, 2H), 6.75 (s, lH), 6.6 (s and d, 2H), 2.3 (s, 3H)

In an analoguos way were synthesized :

No. Starting Material Molstructure yield IH-NMR (DMSO D6) or Rfvalue (solvent) 3 From Il and 3-""16% 9. 20 (s, 1H), hydroxyaniline 8. 95 (s, lH) ; 8. 10 (d, hydroxyaniline H N < ' !' 1H), 7. 40-6. 2 (m, I 11 H), 2. 30 (s, 3H), 2. 25 (s, 3H) 4 From 11 and 2-y"10% 8. 05 (s, 1H), 8. 0 (d, methoxyariiline methoxyaniline IH), 7. 85 (d, lH), 7. 25 N (t, 1H), 7. 20 (m, 2H), 7. 00-6. 5 (s, 1H), 6. 40 (d, 1H), 3. 8 (s, 3H), 2. 30 (s, 3H), 2. 25 (s, 3H) 5 From II and 2-N N-1, 30% 9. 7 (s, lH) ; 8. 15 (d, H aminopyridine " 1H), 8. 1 (d, IH), 7. 75 Ij ï (s, IH), 7. 65-7. 5 (m, 2H), 7. 30-7. 1 (m, 3H), 7. 00 (d, IH), 6. 85 (t, I H), 6. 65 (d, lH), 6. 55 (s, IH), 2. 30 (s, 3H), 2. 25 (s, 3H) 6 From 11 and 36 From II and 3-/23% 9. 55 (s, IH) ; 8. 1 (d, b-1 methoxyaniline \D\ (\ 1H), 7. 35b-H Ij ì 6. 9 (m, 7H), 6. 7 (s, lH), ton 6. 51 (s, lH), 6. 56. 4 (m, 2H9, 2. 30 (s, 3H), 2. 25 (s, 3H)

No. Starting Material Moistructure yield IH-NMR (DMSO D6) or Rfvalue (solvent) 7 From II and 4-N-741% 8. 85 (s, lH) ; 8. 0 (d, morpholinoaniline IH), 8. 1 (d, 1H), 7. 35 Han 7. 15 (m, 5H), 6. 95 (d, 1H), 6. 8 (d, 2H), cud 6. 5 (s, lH), 6. 4 (d, lH), o 3. 7 (m, 4H), 3. 0 (m, 4H), 2. 30 (s, 3H), 2. 25 (s, 3H) 8 From II and 4-N-38% 9. 5 (s, IH) ; 8. 15 (d, aminobenzene-IH), 7. 7-7. 6 (ABsulfonamide j ! J syst., 4H), 7. 35 HN N N A 7. 1 (m, 5H), 7. 0 (d, lH), 6. 75 (s, IH), 6. 6 (d and NH2 s, 2H), 2. 30 (s, 3H), 2. 25 (s, 3H) 9 From II and N- nu 56% 9. 8 (s, lH) ; 8. 45 (s, lH), N aminophenyl) acet- N 8. 05 (d, l H), 7. 45amide 7. 15 (m, 6H), / HN N 6. 95 (d, IH), 6. 6 (s, lH), 6. 55 (s, tir), 6. 5 (d, lH), HN,, 2. 30 (s, 3H), 2. 25 0 (s, 3H), 2. 0 (s, 3H)

No. Starting Material Molstructure yield IH-NMR (DMSO-D6) or Rf-value (solvent) 10 From 11 and N-40% 9, 5 (s, lH), 8. 15 (m and d, 3-amino-N-cyclo-N 2H), 7. 85 (d, IH), propylbenzene-7. 45 (t, lH), 7. 35-7. 15 (m, sulfonamide HN N 4H), 7. 00-6. 85 (m, 2H), 6. 70 (s, 1H), 6. 55 (s and H d, 2H), 2. 30 (s, 3H), 2. 25 (s, 3H), 2. 2 (m, lH), 0. 50. 35 (m, 4H) 11 From II and CH, 56% 9, 45 (s, lH), 8. 15 (s and H, c N3-amino-N-r d, 2H), 7. 75 (d, lH), methylbenzene-'"rT 7. 45 (t, lH), 7. 35 (q, IH), sulfonamide,/.. 7. 30-7. 15 (m, 6H), 7. 00 J) (d, lH), 6. 70 (s, 1H), S N S H ; 6 N~SX 6. 55 (s and d, 2H), 2. 30 (s, 3H), 2. 35 (s, 3H), 2. 25 (s, 3H) 12 From II and 4-[2-"jS"44% 8. 9 (s, 1H), 8. 05 (d, 1H), fluoro-l- (fluoro- (, JY 7. 35 d, 2H), 7. 30 (t, 1H), methyl) ethoxy]- ! l 7. 20 (s, 2H), 6. 95 (d, HN N aniline i 1H), 6. 90 (d, 2H), 6. 55 (s, lH), 6. 50 (s, lH), 0 oLF 6. 45 (d, lH), 4. 84. 5 (m, 5H), 2. 30 (s, 3H), 2. 25 (s, 3H)

No. Starting Material Molstructure yield IH-NMR (DMSO-D6) or Rf-value (solvent) 13From II and 3-N-'73% 8. 9 (s, 1H), 8. 05 (d, 1H), H, C morpholinoamline N 7. 3-6. 9 (m, 7H), 6. 65 N r (s, lH), 6. 50 (m, 3H), HIN N 3. 7 (m, 4H), 3. 05 (m, 4H), 2. 30 (s, 3H), 2. 25 (s, 3H) U C) 0 14 From II and 4- (1H-49% 0. 33 (B) 1, 2, 3-triazol-1-yl)- N aniline HN N 9 {) 15 From II and 3-NCH3 60% 9, 45 (s, IH), 8. 15 (s and HoC Naminobenzene-N d, 2H), 7. 8 (d, 1H), 7. 50sulfonamide in 7. 15 (m, 8H), 7. 00 (d, HN N IH), 6. 70 (s, 1H), 6. 55 (s and d, 2H), 2. 30 (s, 3H), 2. 25 (s, 3H) NH 16 From 11 and 4-43% 12. 3 (s, lH), 9, 50 (s, 1H), aminobenzoic acid 8. 20 (d, 1H), 7. 80 (d, CF 2H), 7. 60 (d, 2H), 7. 20 N (m, 4H), 7. 30-7. 15 (m, NH 4H), 7. 0 (d, lH), 6. 75 ' (s, lH), 6. 6 (d, lH), O OH 6. 55 (s, lH), 2. 30 (s, 3H), 2. 25 (s, 3H)

No. Starting Material Moistructure yield IH-NMR (DMSO-D6) or Rf-value (solvent) N 17 FromIIand4-, 49% 0. 28 (A) HC \ amino-N-methyl-N benzenesulfon-ff1 amide HN N o=so HN, CH, 18 From II andN- (4-/64% 9. 4 (s, IH), 9. 05 (s, IH), Nc N aminophenyl)-8. 20 (d, IH), 7. 40 (d, N methanesulfon-""t. 2H), 7. 30 (t, IH), 7. 2 (s h amide H and d, 2H), 7. 1 (d, 2H), 6. 95 (d, lH), 6. 6 (s, IH), 6. 55 (s, lH), 6. 5 (d, lH), \\ NH Ho 2. 9 (s, 3H), 2. 30 (s, 3H), 2. 25 (s, 3H) 19 From IV and 4-CH3 6% 0. 27 (A) aminobenzamide N HN I NH2 20 From 11 and aniline CH3 29% 9. 10 (s, lH), 8. 10 (d, IH), 7. 50 (d, 2H), 7. 30 (m, N-N 5H), 6. 90 (m, 2H), 6. 60 CH3 (s, lH), 6. 55 (m, 2H), 2. 30 N HNV (s, 3H), 2. 25 (s, 3H) Xi

No. Starting Material Molstructure yield IH-NMR (DMSO-D6) or Rf-value (solvent) 21 From II and 4-34% 9. 00 (s, IH), 8. 10 (d, IH), methyl aniline 7. 30 (m, 5H), 6. 90 (m, 3H), 6. 60 (s, IH), N ? 6. 55 (m, 2H), 2. 30 (s, 3H), r 2. 25 (s, 3H), 2. 20 (s, 3H) 9 CH, 22 From II and 4-ci3 28% 10. 00 (s, 1H), 9, 50 (s, amino-N-phenyl- ( 1H), 8. 20 (d, 1H), 7. 90benzamide CH3 6. 50 (m), 5. 70 (s, tir), ? 1 ? 1 2. 30 (s, 3H), 2. 25 (s, 3H) HO SU 0 0 23 From II and methyl 9% 9. 50 (s, IH), 8. 10 (d, tir), 4-aminobenzoate (tl N 8. 00-7. 00 (m, 8H), 6. 70 rr-CH (s, IH), 6. 55 (m, 2H), 3. 70 (s, 3H), 2. 30 (s, 3H), 2. 25 N N h H ' ", LJ 0 0 24 From IV and 4-.,/x amino-Nmethylbenzene-f ! j HN N sulfonamide O= IO 0=5=0 I HN, CH,

No. Starting Material ! Mo ! structureyield 1H-NMR (DMSO-D6) or Rf-value (solvent) 25 From VI and 4-CH, 29% 9. 35 (s, IH), 8. 25 (d, IH), Naminobeirizamide N 7. 75 (s, 2H and), H, C in 7. 6 (d, 2H), 7. 25 HN N 7. 15 (2d, AB, 4H), (je 7. 05 (NH), 6. 55 (s and d, o ; N H 2 2. 35 (s, 3H), O-NH 2. 3 (s, 3H) 26 FromIVand3-45% 0, 37 (A) I aminobenzenesulfonamide HNXN) HN N 0-/\ NH, 27 From VI and 4-/ 16% 0. 31 (A) aminobenzene H, C H, C sulfonamide il h o=s=o I 29 From In and 4-CH3 2, 50% 7. 80-6. 20 (m,), 3. 00 (m, aminobenzamid lH), 2. 40 (s, 3H), 1. 20 M-N cH rCH, (d, 6H) NI CH3 N' 0 J\H, 0

No. Starting Material Molstructure yield 1H-NMR (DMSO-D6) or Rf-value (solvent) 29 From II and 3-CH3 57% 9, 40 (s, 1H), 8. 10-6. 50 aminobenzamide (m), 2. 30 (s, 3H), 2. 25 (s, N-N 3H) CH3 N 2 0 YN 30 From II and 4-CH3 17, 80% 9, 50 (s, IH), 8. 10 (m, amino-N-methyl- 2H), 7. 60 (m, 4H), 7. 20 benzamide N benzamide NX (m, 3H), 7. 00 (m, IH), N I HN CH3 6. 70 (s, 1H), 6. 50 (m, 2H), 2. 70 (d, 3H), 2. 30 (s, 3H), 2. 25 (s, 3H) HN CH3 31 From II and N- (4-"x H3C aminophenyl)-N, N- D- N dimethylamine I HN N HN N H, C CH 32 From II and 4-x amino-N- (1, I-dioxidotetrahydro-3- [j ! thienyl) benzamide 2' O'-NH 4

No. Starting Material Molstructure yield IH-NMR (DMSO-D6) or Rf-value (solvent) 33 From II and N- (4-,/x : Z,-N aminophenyl)-Nethylacetamide HN HN N CH, CH, 34 From II and l-/x HC facetyl-6-indolin-N amine H N N CH, 35 From II and 4-Nc CH, Cs =A bromoaniline N HN N Br 36 From VI and N- (4-, CH3 aminophenyl) H3C-" methanesulfon-HN N HN N amide LNH HsC 37 From IV and N- (4- N CH3 rr-N aminophenyl)-F' JL F methanesulfon-HN N amide 0 amide Q NH H3C

No. Starting Material Molstructure yield IH-NMR (DMSO-D6) or Rf-value (solvent) 38 From VI and 3-CH3 N ! 0 aminobenzenesulfonamide Hot N HN N H2 39 From VII andN- (4-CH H3 N aminophenyl)-6 methanesulfon-HNN N amide c\NH H3 H30'b 40 From Hand 4-4, 59. 3 (s, lH) ; 8. 2 (d, IH), amino-N, N-di-/1 amino-N, N-di- 7. 6 (AB-syst., 2H), 7. 35ermethylbenzamide 7. 1 (m, 5H), 7. 0 (d, IH), N 6. 75 (s, lH), 6. 6 (m, 2H), ENVY Uo 3. 0 (s, 6H), 2. 30 (s, 3H), H, ccH, 2. 25 (s, 3H) 3 3 41 From VIII and4-F CH3 aminobenzenesulfonamide HN N 0=5=0 H2 42From Vin and 4-F CH3 aminobenzamide HN N 0 N

No. Starting Material Moistructure yield IH-NMR (DMSO-D6) or Rf-value (solvent) 43 From I and N- (4- N-CH3 9, 50 (s, IH), 9. 40 (bs, N aminophenyl)-0' 1H), 8. 10 (d, IH), 8. 00 methanesulfon-HN-"N (d, 1H), 7. 60 (m, 2H), amide Q 7. 30 (m, 3H), 7. 00 (m, 0 H 3H), 6. 60 (m, 3H), 2. 90 H3 (s, 3H), 2. 30 (s, 3H) 44 From I and 4-CH3 9, 50 (s, IH), 8. 10 (m, aminobenzenc-b-0 i 2H), 7. 60 (m, 6H), 7. 10 sulfonamide,"" (m, 4H), 6. 70 (s, 1H), Q 6. 60 (m, 2H), 2. 30 (s, 0$% 0 3H) NH 2 45 From Il and methyl CH3 1, 4 9. 5 (s, IH) ; 8. 45 (s, IH), /1 4-aminophenyl-8. 05 (d, IH), 7. 4-6. 4 (m), N-N carbamate . J-CH, 3. 60 (s, 3H), 2. 35 (s, 3H), N 2. 2 (s, 3H) HN CH3 NH o 9 46 From H and 4-CH3 12, 6 8. 3 (s, IH), 8. 05 (d, IH), amino-3-methyl-7. 80 (s, 1H), 7. 7 (m, IH), N-N CH benzamide N 7. 60 (m, 1H), 7. 5 (m, NH CH, IH), 7. 20 (m, 4H), 7. 00 S (m, 1H), 6. 70 (s, IH), H2N o 6. 50 (m, 2H), 2. 30 (s, 3H), 2. 25 (s, 3H), 2. 20 (s, 3H)

No. Starting Material Molstructure yield IH-NMR (DMSO-D6) or Rf-value (solvent) 47 From Il and CH3 3, 9 9. 6 (s, 1H), 8. 2 (d, 1H), 4- (1-pyrrolidinyl- 7. 7 (AB-syst., 4H), 7. 2 CH sulfonyl) aniline, : C' (m, 4H), 7. 0 (d, IH), NH 6. 75 (s, lH), 6. 6 (m, 1H), 6. 55 (s, 1H), 3. 1 (m, 4H), 00 2. 35 (s, 3H), 2. 25 (s, 3H) 48 From I and 4-N CH3 43% 9, 50 (s, 1H), 8. 10 (m, N N aminobenzamid rot 2H), 7. 80-7. 50 (m, 7H), HN N 7. 20 (d, 1H), 7. 05 (m, (j 2H), 6. 70 (s, tir), 6. 60 o 2 (m, 2H), 2. 30 (s, 3H) 2 49 From TI and ethyl ! 17, 9 9. 5 (s, 2H), 8. 05 (d, IH), 4-aminophenyl-7. 4-7 (m), 6. 6 (m, 2H), N N carbamate NC 3 4. 1 (q, 2H), 2. 35 (s, 3H), Han 2. 2 (s, 3H), 1. 2 (t, 3H) NH CH3 CHEZ 50 From n and 3-OH 27, 3 9, 40 (s, IH), 8. 20 (m, aminocarboxilyc NI 2H), 7. 80 (d, 1H), 7. 50 N acid N N (d, 1H), 7. 40-7. 15 (m, ''' \N c -0 H 5H), 7. 0 (m, IH), 6. 7 (s, lH), 6. 5 (m, 2H), 2. 30 (s, 3H), 2. 25 (s, 3H)

No. Starting Material Molstructure yield IH-NMR (DMSO D6) or Rfvalue (solvent) 51 From II and 3-amino-) sOH 6, 4 10, 4 (s, IH), 9, 40 (s, carboxilyc acid M ! H), 8. 40 (s, IH), 8. 10 MS ss (m, 2H), 7. 80 (d, I H), zon 7. 60 (d, IH), 7. 50 H, C- \N" 7. 15 (m, 6H), 7. 0 (m, tir), 6. 7 (s, lH), 6. 5 (m, 2H), 2. 30 (s, 3H), 2. 25 (s, 3H) 52 From IX and N- (4- CH3 H3 aminophenyl)-H, omethanesulfonamide HN N (I H H3 53 From IX and 4-gH3 N CH3 N aminobenzenesulfon-O amide HN N ho nu Q H2 54 From IX and 4-N CH3 H3 aminobenzamide H J.

HN N 0 NH

No. Starting Material Moistructure yield IH-NMR (DMSO D6) or Rfvalue (solvent) 55 From II and 1, 4-'"/10% 9, 30 (s, 1H), 8. 10 (d, benzenediamine (5 1H), 7. 20 (m, 7H), eq.) Ne 7. 00 (d, 1H), 6. 70 (d, , 2H), 6. 50 (m, 3H), NH Q 2. 30 (s, 3H), 2. 25 (s, S NH2 3H) 56 From V and N- (4- 60% 9, 60 (m, 2H), 8. 30 (m, aminophenyl)-= ( s' 1H), 8. 00 (m, 2H), rY i o methanesulfonamide N H 7. 70 (d, 1H), 7. 40 (m, H H 3H), 7. 10 (d, 2H), 6. 70 (m, 3H), 3. 00 (s, 3H), 2. 30 (s, 3H) 57 From V and 4-amino-N N 0, NH 19% 9, 50 (m, 1H), 8. 20 (m, benzenesulfonamide 3H), 7. 70 (m, 5H), N N 7. 40 (m, IH), 7. 10 (m, N N 2H), 6. 70 (s, IH), 6. 60 (m, 2H), 2. 30 (s, 3H) 58 From I and 1, 4-/-N 2 95% 9, 30 (s, 1H), 8. 00 (m, benzenediamine (5 ''2H), 7. 60 (m, 2H), ro fN-C eq.) 7. 50 (m, 2H), 7. 10 (m, 5H), 6. 60 (m, 4H), 2. 30 (s, 3H)

No. Starting Material Molstructure yield IH-NMR (DMSO D6) or Rfvalue (solvent) c N 59 Fromland4-- !-CH, 73% 9. 50 (s, 1H), 9. 30 (s, amino-N-methyl--H",,-0 ainino-N-methyl-H IH), 8. 10 (s, IH), 8. 00 benzenesulfon- (d, 1H), 7. 60 (m, 2H), amide 7. 30 (m, 3H), 7. 00 (m, 3H), 6. 60 (m, 3H), 3. 00 (s, 3H), 2. 30 (s, 3H) 60 From I and 3- 48% 9. 40 (s, 1H), 8. 10 (s, 5 : 0 aminobenzene-N y 1H), 8. 00 (m, 3H), sulfonamide 7. 70 (m, 3H), 7. 30 (m, 5H), 7. 00 (s, IH), 6. 50 (m, 2H), 2. 30 (s, 3H) 61 Fromland4- V- o 23% 9. 00 (s, 1H), 8. 10 (m, amino-3-methyl--NH, IH), 8. 00 (m, 1H), benzenesulfon-0 7. 70 (m, 6H), 7. 40 (m, j amide/N 1H), 7. 20 (m, 2H), 7. 00 (m, 1H), 6. 60 (m, 2H), 2. 30 (s, 3H), 2. 20 (s, 3H)

table 4 In table 4, the respective solvents are : A : CH2Cl2/MeOH=9 : 1 B : CH2Clz/MeOH=95 : 5

Example 62 : N-[4- ( {4- [3-methyl-l- (3-methylphenyl)-lH-pyrazol-5-yl]-2pyridinyl} amino) phenyl] propanamide

30 mg (0.08 mmol) N-(4-aminophenyl)-N-{4-[3-methyl-1-(3-methylphenyl)-1Hpyrazol-5-yl]-2-pyridinyl} amine are dissolved in 1 mL dichloromethane. 12 mg (0.11 mmol) triethylamine and 10 mg (0.07 mmol) propanoyl chloride are added and the reaction mixture is stirred overnight. The reaction is quenched with water, and the organic materials are dried over magnesium sulfate, filtered and concentrated under vacuum. Chromatography afforded 14 mg ofthe title compound (34% yield).

LC/MS : MS (ESI) : 412 (M+H+) retention time 3.00 min.

In an analogous way were prepared :

No. Starting Material Molstructure yield IH-NMR (DMSO D6) or LC/MS 63 From NX 53% LCMS : MS (ESI) : Nethanesulfonyl 540 (M+Hj retention N// chloride (2 eq.) t time 4, 20 min.

H O. Y O. gjD 64 From 14% 9, 50 (s, 1H), 9. 20 (s, ethanesulfonyl N 1H), 8. 10 (d, 1H), 7. 40 Chloride (l eq.) Q (m, 5H), 7. 20 (d, 2H), ü'Lr N N H 7. 00 (d, IH), 6. 70 (s, 1H), 6. 60 (m, 2H), 3. 05 (q, 2H), 2. 30 (s, 3H), 2. 25 (s, 3H), 1. 30 (t, 3H)

table 5 LC-parameters solution A acetonitrile, solution. B 0, 3g 30% HCI/1 water column oven 40 C ; column Symmetry C18 2, 1 x 150 mm gradient : time [min] % A % B flow [ml/min] 0 10 90 0, 9 3 90 10 1, 2 6 90 10 1, 2

Claims (15)

1. Claims 1. Compounds of general formula (1),

   wherein R1 and R2 represent hydrogen, halogen, Cl-C4-alkyl or Cl-C4-alkoxy, wherein C1-C4-alkyl or Cl-C4-alkoxy can optionally be substituted with up to 3 halogen atoms, R3 represents hydrogen, halogen, N-bound heterocyclyl, hydroxy, C1-C6 alkoxy or C1-C6-alkyl, wherein C1-C6-alkoxy or C1-C6-alkyl can optionally be substituted with up to 3 halogen atoms,

   or R3 represents-NR3''R,-COR3-3 or-S02R, wherein R3-) represents hydrogen, C)-C6-alkyl, C3-C6-cycloalkyl, C6 Clo-aryl, heteroaryl, Cl-C6-alkylcarbonyl, Cl-C6-alkoxycarbonyl, C3-Cg-cycloalkylcarbonyl, C6-Cwarylcarbonyl, heteroarylcarbonyl, Cl-C6-alkylsulfonyl, C3-C8-cycloalkylsulfonyl, C6-Cwarylsulfonyl, heteroarylsulfonyl,

   R3-
2. 2 represents hydrogen, Cl-C6-alkyl, C3-C6-cycloalkyl, C6-Cio-aryl, heteroaryl, Cl-C6-alkylcarbonyl, Cl-C6-alkoxycarbonyl, C3-Cg cycloalkylcarbonyl, C6-C10-arylcarbonyl, heteroarylcarbonyl, C1-C6-alkylsulfonyl, C3-C8-cycloalkylsulfonyl, C6-C10-aryl- sulfonyl, heteroarylsulfonyl,

   R3-3 represents hydrogen, hydroxy, Ci-C6-alkyl, C3-C6-cycloalkyl, Cl-C6-alkoxy, C6-Co-aryloxy, C6-Clo-aryl, heteroaryl, amino, Ci-C6-alkylamino, Cl-C6-dialkylainino, C3-C6-cycloalkyl amino, C3-C6-bis-cycloalkylamino, C6-C10-arylamino, C6-C10 bis-arylamino, heterarylamino, 3-sulfolanylamino, N-bound heterocyclyl, R3-4 represents hydroxy, C1-C6-alkyl, C3-C6-cycloalkyl, C6-C10-aryl, heteroaryl, amino, C]-C6-alkyIamino, Ci-C6-dialkylamino, C3 C6-cycloalkylamino, C3-C6-bis-cycloalkylamino, C6-C10-aryl amino, C6-C10-bis-arylamino, heteroarylamino, N-bound heterocyclyl, and wherein carbon atoms ofR3 can optionally be substituted with up to three halogen atoms, R4 represents hydrogen, halogen or C1-C4-alkyl, or R3 and R4 together with the carbon atoms to which they are attached form a [N-(C1-C6)alkylcarbonyl]-pyrrolidinring R5 represents Cl-C6-alkyl

   A represents carbon or nitrogen, D represents a 5-to 10-membered aromatic ring, which can contain up to
3. 3 heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, or pharmaceutically acceptable salts thereof.

   2. Compounds of general formula (I) according to claim 1, wherein R1 and R2 represent hydrogen, halogen, Ci-C4-a ! kyl or Cl-C4-alkoxy, wherein Cl-C4-alkyl or Ci-C4-a ! koxy can optionally be substituted with up to 3 halogen atoms, R3 represents hydrogen, halogen, CrC6-alkyl, which can optionally be substituted with up to 3 halogen atoms, or R3 represents C1-C6-alkylcarbonylamino, C1-C6-dialkylcarbonylamino

   amino, C6-Cio-arylcarbonylamino, C3-Cg-cycloalkylcarbonylamino, Ci-C6-alkylamino, Cl-C6-dialkylamino, C3-C6-cycloalkylamino, C6 C10-arylamino, Cl-C6-alkoxycarbonylamino, carboxyl, Cl-C6-alkoxy- carbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, CrC6-diaIkyl- aminocarbonyl, C6-arylaminocarbonyl, 3-sulfolanylaminocarbonyl,

   Cl-C6-alkylsulfonylamino, aminosulfonyl, Cl-C6-alkylaminosulfonyl, C]-C6-diaIky ! aminosuIfbnyI, C3-Cs-cycloalkyIaminosuIfbnyl, Npyrrolidinylsulfonyl, N-morpholinyl, 1, 2, 3-triazol, hydroxy, Cl-C6

   alkoxy, wherein CrC6-alkoxy can optionally be substituted with up to 3 halogen atoms, R4 represents hydrogen orC)-C4-alkyl, R represents methyl, A represents carbon or nitrogen, D represents a phenyl, o-pyridyl, benzofuranyl, indolyl or thiophenyl

   ring, and wherein substituents R3 and/or R4 are in meta-or para-position relative to the exocyclic amino group.

   Compounds of general formula (I) according to claim 1 or 2, wherein

   R1 and R2 represent hydrogen, halogen, Cl-C4-alkyl or Ci-C4-aIkoxy, wherein C}-C4-alkyl or Ci-C4-alkoxy can optionally be substituted with up to 3 halogen atoms, R3 represents hydrogen, halogen, Cl-C6-alkyl, which can optionally be substituted with up to 3 halogen atoms, or

   R3 represents Ct-C6-alkylcarbonylamino, amino, Cl-C6-alkylamino, Cr C6-dialkylamino, aminocarbonyl, Ci-Ce-alkylaminocarbonyl, Cl-C6 dialkylaminocarbonyl, C6-arylaminocarbonyl, C1-C6-alkylsulfonyl amino, aminosulfonyl, Cl-C6-alkylaminosulfonyl, Cl-C6-dialkyl- aminosulfonyl, Ct-C6-alkylsulfony ! amino, R4 represents hydrogen or C1-C4-alkyl, R5 represents methyl, A represents carbon or nitrogen, D represents phenyl.
4. 4. Compounds of general formula (I) according to claim 1, wherein A represents carbon.
5. 5. Compounds of general formula (I) according to claim 1, wherein R5 represents methyl.
6. 6. Compounds of general formula (I) according to claim 1, wherein R I represents methyl or fluoro.
7. 7. Compounds of general formula (I) according to claim 1, wherein R3 represents aminosulfonyl, aminocarbonyl or methylsulfonyl amino.
8. 8. Compounds of general formula (I) according to claim 1, wherein substituents R3 and/or R4 are in para-position relative to the exocyclic amino group.
9. 9. A process for synthesizing the compounds of general formula (I) according to

   claim 1, characterized in that compounds of general formula (11)

   are reacted with compounds of general formula (111)

   to yield compounds of general formula (I).
10. 10. The composition containing at least one compound of general formula (I) according to claim 1 and a pharmacologically acceptable diluent.
11. 11. A composition according to claim 10 for the treatment of acute and chronic inflammatory processes.
12. 12. The process for the preparation of compositions according to claim 10 and 11 characterized in that the compounds of general formula (I) together with cu stomary auxiliaries in brought into a suitable application form.
13. 13. Use compounds of general formula (I) according to claim 1 for the preparation of medicaments.
14. 14. Use according to claim 13 for the preparation of medicaments for the treatment of acute and chronic inflammatory processes.
15. 15. Use according to claim 14, wherein the process is COPD.